Identification of clofibric acid as a SYVN1 ligand for PROTAC development

Abstract

Targeted protein degradation (TPD) is an emerging therapeutic modality for numerous diseases. PROteolysis-TArgeting Chimeras (PROTACs) represent a potentially generalizable strategy to achieve TPD. A PROTAC is composed of a ligand for a protein of interest, a linker and a ligand for E3 ligase. As such, PROTACs can bring the E3 ligase into the close proximity of a protein target leading to polyubiquitination followed by target protein degradation. While the human genome encodes over 600 E3 ligases, only a handful of them have been harnessed for developing PROTACs. In order to expand the repertoire of E3 ligases for PROTAC development, we developed clickable photoaffinity probes based on clinically used drugs and metabolites to identify potential E3 ligases as the targets. In this paper, we report the discovery of clofibric acid with a molecular weight of only 214 Daltons as a ligand for synoviolin (SYVN1). We demonstrate its utility by developing clofibric acid-based BRD4 PROTACs. The linker length and architecture play a critical role in target degradation efficiency. The clofibric acid-derived BRD4 PROTACs achieve selective BRD4 degradation in a SYVN1-dependent manner. Our findings establish clofibric acid as a robust addition to the TPD toolbox, offering a novel E3 ligase recruitment strategy for the development of next-generation degraders. TOC Graphics O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=90 SRC="FIGDIR/small/701774v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@776850org.highwire.dtl.DTLVardef@1616bd0org.highwire.dtl.DTLVardef@ed3e03org.highwire.dtl.DTLVardef@18271e7_HPS_FORMAT_FIGEXP M_FIG C_FIG